This invention relates to 2-thioxobenz[cd]indole-1(2H)-acetic acid derivatives, therapeutically acceptable salts thereof, a process for their preparation and to pharmaceutical compositions thereof. The derivatives are potent inhibitors of lens aldose reductase which render them beneficial for the treatment of diabetes mellitus and associated conditions.
For many years diabetes mellitus has been treated with two established types of drugs, namely insulin and oral hypoglycemic agents. These drugs have benefited hundreds of thousands of diabetics by improving their well-being and prolonging their lives. However, the resulting longevity of diabetic patients has led to complications such as neuropathy, nephropathy, retinopathy, atherosclerosis and cataracts. These complications have been linked to the undesirable accumulation of sorbitol in diabetic tissue, which in turn result from the high levels of glucose characteristic of the diabetic patient.
In mammals, including humans, the key enzyme involved in the conversion of hexoses to polyols (the sorbitol pathway) is aldose reductase. J. H. Kinoshita and collaborators, see J. H. Kinoshita, et al., Biochem. Biophys. Acta., 158, 472 (1968) and references cited therein, have demonstrated that aldose reductase plays a central role in the etiology of galactosemic cataracts by effecting the conversion of galactose to dulcitol (galactitol) and that an agent capable of inhibiting aldose reductase can prevent the detrimental accumulation of dulcitol in the lens. Furthermore, a relationship between elevated levels of glucose and an undesirable accumulation of sorbitol has been demonstrated in the lens, peripheral nervous cord and kidney of diabetic animals, see A. Pirie and R. van Heyningen, Exp. Eye Res., 3, 124 (1964); L. T. Chylack and J. H. Kinoshita, Invest. Ophthal., 8, 401 (1969) and J. D. Ward and R. W. R. Baker, Diabetol., 6, 531 (1970).
A number of benz[cd]indoles are described and exemplified in the following reports: Chemical Abstracts, 88, 21753e (1978) citing Zh. Obshch. Khim., 47, 2042 (1977); Chemical Abstracts, 84, 107080n (1976) citing Ger. Offen., 2,429,760, Jan. 15, 1976; Chemical Abstracts, 66, 46327c (1967) citing U.S.S.R. Pat. No. 183,756, July 9, 1966; Chemical Abstracts, 82, 97936p (1975) citing U.S.S.R. Pat. No. 445,646, Oct. 5, 1974; Chemical Abstracts, 78, 29537b (1973) citing Zh. Org. Khim., 8, 2177-81 (1972); A. Brach, U.S. Pat. No. 3,386,986, June 4, 1968; Chemical Abstracts, 71, 82627n (1969) citing Ivz. Akad. Nauk. SSSR, Ser. Khim., (6), 1390-2 (1969); Chemical Abstracts, 89, 163333n (1978) citing Zh. Org. Khim., 14, 1095-7 (1978); and S. Dutt, J. Chem. Soc., 224 (1923). The compounds of the above reports are distinguished from the compounds of this application by having different chemical structures, and by not being indicated for use as inhibitors of lens aldose reductase.
Another different chemical ring system, 1,3-dioxo-1H-benz[de]isoquinoline-2(3H)-acetic acid and derivatives thereof are reported to be inhibitors of lens aldose reductase by D. Dvornik et al., Science, 182, 1146 (1973) and K. Sestanj et al., U.S. Pat. No. 3,821,383, June 27, 1974; K. Sestanj, U.S. Pat. No. 4,254,108, Mar. 3, 1981; and K. Sestanj, U.S. Pat. No. 4,254,109, Mar. 3, 1981.